Paradoxically, the drug product most commonly used to treat opioid addiction is also subject to patient abuse to the extent that patient deaths are regularly reported. Indeed, the brain's receptor site for opiates is also receptive to methadone. Perhaps unfortunately, methadone is not metabolized as quickly as other opiate related compounds and typically remains in the body for more than twenty-four hours. As the drug abuser seeks the “high”, or drug induced euphoria, overdose is a frequent result. The United States Food and Drug Administration has recognized the problems associated with methadone overdose and in 2006 issued an adverse events advisory. The agency said “severe life-threatening adverse events such as respiratory depression, cardiac arrhythmias and, in some cases, death can result from unintentional overdoses of methadone”. The agency also added, “such events can also be caused by certain drug interactions and the drug's cardiac toxicities”.
Currently commercially available forms of methadone utilize, as a drug substance, the highly water-soluble methadone hydrochloride active pharmaceutical ingredient to formulate, as a drug product, the dosage forms.
It has long stood as conventional wisdom within the art that within a select group of counterions, referred to collectively as “pharmaceutically acceptable salts”, there is no advantage to be expected from deviating from preparation of hydrochloride salts. This understanding is clearly recorded in Cruz et al. (US PreGrant Publication No. 2005/0158382) wherein specifically stated is a “pharmaceutically acceptable salt” is “those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and, as such, they are the pharmacological equivalent of the base form of the active agent”. Based on the teachings of Cruz, one of skill in the art would have no reason to consider any of the over 90 (pharmaceutically acceptable) salts as being different from the others. In fact, one of skill in the art would elect the salt based on convenience since the pharmacological activity would be expected to be the equivalent to the base form.
There remains a mandated, yet unsolved, need for drug products which can provide a dose of methadone to the patient wherein the dose is provided in such a way as to thwart abuse. The present invention satisfies such a need by altering the drug substance to directly control the properties of the drug substance in a manner which is contrary to expectations in the art.